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Home , Amenorrhea

:​ A Systematic Approach to Diagnosis and Management David A. Klein, MD, MPH; Scott L. Paradise, MD; and Rachel M. Reeder, MD Fort Belvoir Community Hospital, Fort Belvoir, Virginia

Menstrual patterns can be an indicator of overall health and self-perception of well-being. Primary amenorrhea, defined as the lifelong absence of menses, requires evaluation if has not occurred by 15 years of age or three years post- . Secondary amenorrhea is characterized by cessation of previously regular menses for three months or previously irregular menses for six months and warrants evaluation. Clinicians may consider etiologies of amenorrhea categorically as outflow tract abnormalities, primary ovarian insufficiency, hypothalamic or pituitary disorders, other endocrine gland disor- ders, sequelae of chronic disease, physiologic, or induced. The history should include menstrual onset and patterns, eating and exercise habits, presence of psychosocial stressors, body weight changes, medication use, galactorrhea, and chronic illness. Additional questions may target neurologic, vasomotor, hyperandrogenic, or thyroid-related symptoms. The physical examination should identify anthropometric and pubertal development trends. All patients should be offered a test and assessment of serum follicle-stimulating hormone, , , and thyroid-stimulating hormone levels. Additional testing, including karyotyping, serum evaluation, and pelvic or brain imaging, should be indi- vidualized. Patients with primary ovarian insufficiency can maintain unpredictable function and may require hormone replacement therapy, contraception, or services. Functional hypothalamic amenorrhea may indicate disordered eating and low bone density. Treatment should address the underlying cause. Patients with polycystic ovary syndrome should undergo screening and intervention to attenuate metabolic disease and risk. Amenorrhea can be associ- ated with clinically challenging pathology and may require lifelong treatment. Patients will benefit from ample time with the clinician, sensitivity, and emotional support. (Am Fam Physician. 2019;​100(1):​39-48. Copyright © 2019 American Academy of Family Physicians.)

Menstrual patterns can be an indicator of overall health Secondary amenorrhea is the cessation of previously status and self-perception of well-being.1,2 A broad dif- regular menses for three months or previously irregu- ferential is important to avoid missing rare or emergent lar menses for six months and warrants evaluation.1,3,6 pathology because many underlying conditions can pres- , the lack of for intervals ent as amenorrhea.3 Primary amenorrhea is the lifelong longer than 35 days in adults or 45 days in adolescents, is absence of menses.3 Evaluation should be considered if approached similarly.1,3,6-8 menarche has not occurred by 15 years of age or three Clinicians should offer a safe and welcoming environ- years post-thelarche.1,4 Lack of any pubertal development ment where patients feel comfortable discussing repro- by 13 years of age should prompt investigation for delayed ductive health concerns by establishing confidentiality, .4,5 building rapport, and allotting the requisite time needed to talk about possible long-term treatments and sequelae of chronic medical conditions. Preventive health visits should Additional content at https://www.aafp.org/afp/2019/0701/ include education, such as measurement p39.html. from the first day of menstruation to the first day of the CME This clinical content conforms to AAFP criteria for next cycle;​ intervals are typically 21 to 34 days.1 Smart continuing medical education (CME). See CME Quiz on phone apps (e.g., Clue) are useful for determining patterns.9 page 13. Etiologies of amenorrhea can be categorized as: ​outflow Author disclosure:​ No relevant financial affiliations. tract abnormalities, primary ovarian insufficiency, hypotha- Patient information:​ Handouts on this topic are available lamic or pituitary disorders, other endocrine gland disor- at https://​family​doctor.org/condition/amenorrhea/, https://​ 3,6 family​doctor.org/condition/female-athlete-triad/, and ders, sequelae of chronic disease, physiologic, or induced 1-3,5,6,10-12 https://​www.aafp.org/afp/2013/0601/p781-s1.html. (Table 1 ). Abnormal pelvic anatomy is important to consider in the evaluation of primary amenorrhea.3 All

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TABLE 1

Select Causes of Amenorrhea* Outflow tract abnormalities Hypothalamic or pituitary disorders (continued) Other endocrine gland disorders Acquired Constitutional delay of puberty Adrenal insufficiency Cervical stenosis Empty sella syndrome Androgen-secreting tumor (e.g., ovarian Intrauterine adhesions Functional (overall energy deficit or ) or adrenal) Congenital Cushing syndrome 5α-reductase deficiency Stress Diabetes mellitus, uncontrolled Androgen insensitivity syndrome Vigorous exercise Late-onset congenital adrenal hyperplasia Weight loss Polycystic ovary syndrome (multifactorial) Müllerian agenesis Gonadotropin deficiency (e.g., ) Transverse Hyperprolactinemia Amenorrhea attributed to chronic disease Primary ovarian insufficiency Adenoma () Celiac disease Acquired Chronic kidney disease Inflammatory bowel disease Autoimmune Medications or illicit drugs (e.g., antipsychotics, Other chronic disease Chemotherapy or radiation opiates) Physiologic or induced Congenital Physiologic (pregnancy, stress, exercise) (other than Infarction (e.g., Sheehan syndrome) Contraception ) Infiltrative disease (e.g., ) Exogenous Turner syndrome or variant Infection (e.g., meningitis, tuberculosis) Hypothalamic or pituitary disorders Medications or illicit drugs (e.g., cocaine) Pregnancy Autoimmune disease Trauma or surgery Brain radiation Tumor (primary or metastatic)

*—Conditions may span multiple categories. Adapted with permission from Klein DA, Poth MA. Amenorrhea: ​an approach to diagnosis and management. Am Fam Physician. 2013;​87(11):​782, with additional information from references 1, 2, 5, 6, and 10 through 12.

causes of secondary amenorrhea may present as primary presence of circulating .6 Atrophic vaginal mucosae amenorrhea and the evaluation is similar (Figures 1 and 2).3 suggests low estrogen, and a shortened vagina may indicate outflow tract obstruction or Müllerian agenesis.6,16,17 Signs of Evaluation virilization suggest hyperandrogenic conditions. Evidence HISTORY of dysmorphism may suggest a congenital syndrome.6,10,17 A detailed history should include menstrual patterns (if any), pregnancy and breastfeeding history, eating and LABORATORY AND OTHER TESTING exercise habits, psychosocial stressors (e.g., perfectionist In all cases, pregnancy should be excluded with a pregnancy behaviors), changes in body weight, fractures, medication test.2,3,6 Serum patterns of follicle-stimulating hormone, or substance use, chronic illness, and timing of breast and luteinizing hormone, prolactin, and thyroid-stimulat- pubic hair development2,3,6 (Table 21-3,5,6,10-12). Galactorrhea, ing hormone identify most endocrine causes of amenor- headaches, or visual field defects can indicate hypothalamic rhea2,3,6,10-12 (Figure 13). Serum free and total testosterone, or pituitary disease,13,14 and acne or hirsutism can indicate and dehydroepiandrosterone sulfate levels may be obtained .15 Vasomotor symptoms such as hot if there is evidence of hyperandrogenism8,15,18,19 (Table flashes or night sweats may indicate primary ovarian insuf- 32,5,6,10-12). A 17-hydroxyprogesterone level collected at 8 ficiency.10 A family history should include the age of men- a.m. assesses for late-onset congenital adrenal hyperpla- arche of relatives and any chronic disease history.2,3 sia.2,15 Low anti-Müllerian hormone correlates with ovarian reserve and may indicate primary ovarian insufficiency or PHYSICAL EXAMINATION menopause (Table 4).2 Clinicians should review trends in height, weight, and body Karyotyping should also be considered in patients of mass index.2,3 Normal indicates the short stature to evaluate for Turner syndrome.6,20 Patients

40 American Family Physician www.aafp.org/afp Volume 100, Number 1 ◆ July 1, 2019 AMENORRHEA FIGURE 1

Perform history and physical examination (Table 2)

Pregnancy test; serum LH, FSH, TSH, and prolactin levels; pelvic ultrasonography or other laboratory testing if clinically indicated

Pregnancy test positive: pregnant, treat as appropriate present? Abnormal TSH level: order thyroid func- tion tests and treat thyroid disease Abnormal prolactin level: magnetic resonance imaging of the pituitary to exclude adenoma; review medications

Yes No

Karyotype; free and total testosterone levels

Low FSH and LH levels* Normal FSH and LH levels* Elevated FSH and LH levels*

Functional hypothalamic Consider outflow tract Primary ovarian 46,XX, expect 46,XY, expect amenorrhea (if energy obstruction; also consider all insufficiency female-range serum male-range serum deficit), constitutional delay other causes of amenorrhea testosterone level testosterone level of puberty; rarely primary with normal gonadotropin gonadotropin-releasing levels (Figure 2) Order karyotype to evalu- hormone deficiency ate for Turner syndrome or Müllerian Androgen insensitivity syndrome presence of Y chromatin agenesis or 5α-reductase deficiency

Diagnosis of primary amenorrhea.

FSH = follicle-stimulating hormone;​ LH = luteinizing hormone; ​TSH = thyroid-stimulating hormone. *—May be repeated in one month if needed to clarify diagnosis. Adapted with permission from Klein DA, Poth MA. Amenorrhea:​ an approach to diagnosis and management. Am Fam Physician. 2013;87(11):​ 784.​

with this syndrome require screening for cardiac and renal Differential Diagnosis and Management defects, neurocognitive and behavior disorders, hypothy- OUTFLOW TRACT ABNORMALITIES roidism, and hearing loss, and generally require hormone Outflow tract abnormalities are generally associated with therapies for puberty induction and growth, often in con- 46,XX chromosomal patterns and normal pubertal pro- sultation with a pediatric endocrinologist.17,20,21 gression. Müllerian agenesis occurs in approximately one Pelvic ultrasonography or magnetic resonance imaging in 5,000 females and in 15% of females diagnosed with pri- (MRI) can identify abnormal reproductive anatomy or mary amenorrhea.25,26 It is characterized by the abnormal detect an androgen-secreting tumor.2,15 MRI of the brain development of reproductive anatomy and is associated with can identify pituitary and other tumors.2,6,13 Dual energy urologic and skeletal malformations.16,25 Transverse septum x-ray absorptiometry can establish baseline fracture risk in and imperforate hymen may present with cyclic . patients with concerns for primary ovarian insufficiency Intrauterine adhesions can occur after endometrial instru- or functional hypothalamic amenorrhea.2,22 A hormonal mentation and are corrected using hysteroscopy. Cervical challenge can be used after excluding pregnancy to deter- stenosis can occur after cervical procedures, radiation, or mine the presence of functioning anatomy;​ however, the vaginal birth.6,27 predictive value of this test on adequate endometrial estro- Androgen insensitivity syndrome is characterized by the gen exposure is inconsistent.3,17,23 A common regimen for resistance of peripheral tissues to testosterone in patients a hormonal challenge is 10 mg of medroxyprogesterone with 46,XY chromosomal patterns.28-30 Patients with 5α- (Provera) orally per day for 10 days; ​withdrawal bleeding reductase deficiency are phenotypic females that develop may indicate estrogen exposure (e.g., polycystic ovary syn- male secondary sex characteristics at puberty. Both of these drome [PCOS]) and lack of bleeding may indicate a low- rare conditions are confirmed by genetic analysis or enzyme estrogen condition.2,24 assays.28 Prophylactic gonadectomy may require evaluation

July 1, 2019 ◆ Volume 100, Number 1 www.aafp.org/afp American Family Physician 41 AMENORRHEA FIGURE 2

Perform history and physical examination (Table 2) Review medications including contraceptives and illicit drugs

Pregnancy test; serum LH, FSH, TSH, and prolactin levels; pelvic ultrasonography or other laboratory testing if clinically indicated

Pregnancy test positive: preg- Normal or low FSH or LH levels* Elevated FSH and LH levels* nant, treat as appropriate Repeat in one month; consider Abnormal TSH level: order thyroid func- serum level tion tests and treat thyroid disease Primary ovarian insufficiency, natural menopause; Abnormal prolactin level: MRI of the pituitary order karyotype, especially if patient is of short to exclude adenoma; review medications stature, to rule out Turner syndrome or variant

Evidence of disordered Evidence of high intracranial Evidence of hyperandrogenism History of obstetric or gynecologic pro- eating, excessive exercise, pressure (e.g., headache, cedures; consider hormonal induction or poor nutritional status vomiting, vision changes) of withdrawal bleed or hysteroscopy to Order serum testosterone, DHEA-S, evaluate for intrauterine adhesions 17-hydroxyprogesterone testing Most likely functional Consider MRI of head to hypothalamic amenorrhea evaluate for neoplasm but consider chronic illness

Elevated 17-hydroxyprogesterone level Consistent with polycystic ovary syndrome Rapid onset of symptoms or very high serum androgen levels; consider adrenal and ovarian Consider late-onset con- Screen for metabolic syn- imaging to evaluate for tumor genital adrenal hyperplasia drome; treat accordingly

Diagnosis of secondary amenorrhea.

DHEA-S = dehydroepiandrosterone sulfate;​ FSH = follicle-stimulating hormone;​ LH = luteinizing hormone;​ MRI = magnetic resonance imaging;​ TSH = thyroid-stimulating hormone. *—May be repeated in one month if needed to clarify diagnosis. Adapted with permission from Klein DA, Poth MA. Amenorrhea:​ an approach to diagnosis and management. Am Fam Physician. 2013;87(11):​ 785.​

by a pediatric urologist based on malignancy risk and Patients diagnosed with primary ovarian insufficiency patient or guardian preferences.31 should be offered testing forFMR1 gene premutation, which confers the risk of fragile X syndrome in children.10,11,33,34 PRIMARY OVARIAN INSUFFICIENCY Testing for thyroid and adrenal antibodies and annual or Primary ovarian insufficiency affects approximately one in biennial screening for may be considered 100 females and is defined by follicle dysfunction or deple- given how often these conditions coexist.10,11,35 tion.10,17,32 It is diagnosed in patients younger than 40 years Hormone replacement therapy (HRT) may reduce associ- with two serum follicle-stimulating hormone levels in the ated vasomotor symptoms, bone mineral density loss, and menopausal range obtained at least one month apart.10,17 cardiovascular risk and should be continued until the age Vasomotor symptoms and vaginal dryness are common.10,11 of natural menopause (50 to 51 years).3,20,36-39 A common Most cases are idiopathic; ​however, irradiation, chemo- post-pubertal regimen of HRT is 100 mcg of daily transder- therapy, infections, tumors, autoimmune processes, and mal estradiol or 0.625 mg of daily oral conjugated , chromosomal irregularities can also cause primary ovarian adding 200 mg of micronized oral progesterone daily for 12 insufficiency.10 A karyotype is abnormal in approximately days each month.3,37,38 Transdermal estrogen may be asso- one-third of patients with primary amenorrhea, and it should ciated with lower venous thromboembolism risk than oral be offered to all patients with a diagnosis of primary ovarian formulations.40 It is also reasonable to recommend 1,200 mg insufficiency to identify Turner syndrome (or variants).10,21 of calcium daily and 1,000 IU of vitamin D daily with

42 American Family Physician www.aafp.org/afp Volume 100, Number 1 ◆ July 1, 2019 AMENORRHEA TABLE 2

Findings in the Evaluation of Amenorrhea Findings Associations

History Chemotherapy or radiation Impairment of specific organ or structure, (e.g., brain, pituitary, ovary) Family history of early or delayed menarche Constitutional delay of puberty Galactorrhea Pituitary tumor Hirsutism, acne Hyperandrogenism, PCOS, ovarian or adrenal tumor, CAH, Cushing syndrome Illicit or prescription drug use Multiple associations, consider effect on prolactin Loss of smell (anosmia) Kallman syndrome (GnRH deficiency) Menarche and menstrual history Primary vs. secondary amenorrhea Sexual activity Pregnancy Significant headaches or vision changes Central nervous system tumor, empty sella syndrome Temperature intolerance, palpitations, diarrhea, consti- Thyroid disease pation, tremor, depression, skin changes Vasomotor symptoms (e.g., hot flashes or night sweats) Primary ovarian insufficiency, natural menopause Weight loss, excessive exercise, poor nutrition, psycho- Functional hypothalamic amenorrhea social distress, diets

Physical examination Abnormal thyroid examination Thyroid disorder Acanthosis nigricans or skin tags Hyperinsulinemia (PCOS) Anthropomorphic measurements;​ growth charts Multiple associations; ​Turner syndrome, constitutional delay of puberty Body mass index High: ​ PCOS Low:​ Functional hypothalamic amenorrhea Bradycardia Functional hypothalamic amenorrhea (e.g., ) Breast development (normal progression) Presence of circulating estrogen* Dysmorphic features (e.g., webbed neck, short stature, Turner syndrome low hairline) Male pattern baldness, increased facial hair, acne Hyperandrogenism, PCOS, ovarian or adrenal tumor, CAH, Cushing syndrome Pelvic examination Absence or abnormalities of or uterus Rare congenital causes including Müllerian agenesis or androgen insensitivity syndrome Clitoromegaly Androgen-secreting tumor; ​CAH;​ 5α-reductase deficiency Presence of transverse septum or imperforate hymen Outflow tract obstruction Reddened or thin vaginal mucosa Decreased endogenous estrogen Sexual maturity rating abnormal Turner syndrome, constitutional delay of puberty, rare causes Striae, buffalo hump, central obesity, hypertension Cushing syndrome

CAH = congenital adrenal hyperplasia;​ GnRH = gonadotropin-releasing hormone; ​PCOS = polycystic ovary syndrome. *—Absence of breast buds may not indicate nonfunctioning or future functionality. Adapted with permission from Klein DA, Poth MA. Amenorrhea: ​an approach to diagnosis and management. Am Fam Physician. 2013;​87(11):​783, with additional information from references 1, 2, 5, 6, and 10 through 12.

regular weight-bearing exercises to maintain bone mineral patients and families. Clinicians should offer ample time, density in accordance with guidelines for postmenopausal sensitivity, and emotional support to the patient.11 women.10,41 Approximately 10% of females diagnosed with primary HYPOTHALAMIC AND PITUITARY CAUSES ovarian insufficiency retain fertility.10 HRT may not ade- Functional Hypothalamic Amenorrhea. Functional hypo- quately suppress ;​ therefore, barrier or intrauter- thalamic amenorrhea is a disorder of chronic ine contraceptives may augment HRT for contraceptive caused by suppression of the hypothalamic-pituitary axis purposes.10,38,42 Combined hormonal contraceptives may be from body weight loss, excessive exercise, or stress and may substituted for HRT to adequately prevent pregnancy and result in infertility or bone density loss.2,44-46 The pathology provide the noncontraceptive benefits of HRT;​ this approach is similar to the female athlete triad; ​both are character- requires higher doses of estrogen, which may confer addi- ized by menstrual dysfunction, low energy availability, and tional venous thromboembolic risk.38,43 A primary ovarian decreased bone mineral density.2,22,46 Although functional insufficiency diagnosis introduces long-term challenges for hypothalamic amenorrhea is a diagnosis of exclusion,

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evaluation typically reveals low or low-normal TABLE 3 serum-luteinizing hormone and follicle-stimu- lating hormone levels and low serum estradiol.2 Laboratory and Radiographic Testing in the Bone mineral density testing should be con- Evaluation of Amenorrhea sidered after six months of amenorrhea, severe Findings Associations nutritional deficit, or history of .2,22

Laboratory testing (refer to local reference values) Treatment should correct the underlying cause 17-hydroxyprogesterone level High:​ late-onset CAH to restore ovulatory function through behav- (collected at 8 a.m.) ior change, nutritional repletion (e.g., caloric intake, vitamin D), stress reduction, and weight Anti-Müllerian hormone High:​ Functional hypothalamic amenor- 2,22,46 rhea, PCOS gain. A multidisciplinary team including Low:​ Primary ovarian insufficiency a clinician, nutritionist or registered dietician, and therapist may be optimal.2,22 Patients with Complete blood count and Abnormal: chronic disease (e.g., elevated severe bradycardia, hypotension, orthostasis, or metabolic panel liver enzymes in functional hypothalamic amenorrhea) electrolyte abnormalities may require inpatient treatment.2 A return to play tool to guide recom- Estradiol Low:​ Poor endogenous estrogen produc- tion (suggestive of poor current ovarian mendations for athletes is provided in eTable A. function) Combined oral contraceptives have not been shown to improve bone density; ​however, after Follicle-stimulating hormone High:​ Primary ovarian insufficiency;​ and luteinizing hormone Turner syndrome a reasonable trial of nonpharmacologic ther- Low:​ Functional hypothalamic amenorrhea apy (i.e., six to 12 months), clinicians may Normal:​ PCOS;​ intrauterine adhesions;​ recommend short-term use of transdermal 17β- multiple others estradiol (e.g., 100-mcg patch if bone age is 15 years or older) and cyclic oral progestin (e.g., Free and total testosterone;​ High:​ Hyperandrogenism, PCOS, ovar- dehydroepiandrosterone sulfate ian or adrenal tumor, CAH, Cushing medroxyprogesterone, 2.5 mg daily, 10 days per syndrome month) for this purpose as it avoids first-pass liver metabolism.2,46-48 Hormonal contracep- Karyotype Abnormal: ​Turner syndrome, rare chro- mosomal disorders tives may mask underlying pathology but should be considered for patients at risk of pregnancy Pregnancy test Positive:​ Pregnancy, ectopic pregnancy because ovulation may precede menstruation.2 Prolactin High: ​, medications, The Endocrine Society recommends against bis- hypothyroidism, other neoplasm phosphonate use in this population.2 Thyroid-stimulating hormone High:​ Hypothyroidism Hyperprolactinemia. Elevated serum pro- Low: ​ lactin may induce amenorrhea by inhibiting gonadotrophs. Common causes include medi- Radiographic testing cation use (e.g., antipsychotics), pregnancy, and Dual energy x-ray absorptiometry Evaluation of fracture risk pituitary adenoma.13,14 Most patients with ele- MRI of the adrenal glands Androgen-secreting adrenal tumor vated serum prolactin will require MRI of the pituitary unless prolactin levels collected at least MRI of the brain (including sella)* Tumor (e.g., microadenoma) three days after discontinuing inciting medica- Pelvic organ ultrasonography or Morphology of pelvic organs, polycystic tions have normalized.14 The risk of withdraw- magnetic resonance imaging ovarian morphology, androgen-secreting ing medications (e.g., psychosis) may exceed the ovarian tumor benefits (e.g., bone health).14 Symptomatic pro- CAH = congenital adrenal hyperplasia;​ MRI = magnetic resonance imaging;​ lactinomas may be treated with dopamine ago- PCOS = polycystic ovary syndrome. nists or resection.13,14 *—Clinicians may need to specify the need for pituitary (sella) cuts and contrast. Other Central Nervous System Causes. Indications for magnetic resonance imaging include severe or persistent head- aches, persistent vomiting (not self-induced), lateralizing neurologic signs, clini- Amenorrhea may be caused by hypothalamic- cal signs or laboratory abnormalities to suggest pituitary hormone deficiency or pituitary axis damage through inflammation, excess, or change in vision, thirst, or urination.2 ischemia, infiltration, infection, or trauma. Dis- Information from references 2, 5, 6, and 10 through 12. orders affecting pubertal development, includ- ing gonadotropin-releasing hormone deficiency

44 American Family Physician www.aafp.org/afp Volume 100, Number 1 ◆ July 1, 2019 AMENORRHEA

TABLE 4

Interpretation of Common Laboratory Studies in the Evaluation of Amenorrhea* LH (IU LH/ FSH (IU 17-OHP AMH DHEA-S Estradiol per L) FSH per L) Prolactin Testosterone TSH

Congenital adrenal High Normal High Low < 15 > 1 < 10 Normal High Normal hyperplasia normal

Functional hypotha­ ­ Normal High Normal Low < 10† ~ 1 < 10† Low Low normal Low lamic amenorrhea normal normal

Hyperprolactinemia Normal Normal Normal or Low < 10 > 1 < 10 High Normal High or slightly high normal

Menopause Normal Low Normal Low > 15 < 1 > 15 Normal Low normal Normal

Polycystic ovary Normal Normal High Low < 15 > 1 < 10 High High or high Normal syndrome or high normal normal normal

Primary ovarian Normal Low Normal Low > 15 < 1 > 15 Normal Low normal Normal insufficiency

17-OHP = 17-hydroxyprogesterone;​ AMH = anti-Müllerian hormone;​ DHEA-S = dehydroepiandrosterone-sulfate;​ FSH = follicle-stimulating hor- mone;​ LH = luteinizing hormone; ​TSH = thyroid-stimulating hormone. *—Clinicians should generally interpret these serum laboratory levels in the context of local reference ranges. Specific ranges for some tests are pro- vided to improve diagnostic accuracy between conditions, but should be interpreted in the appropriate clinical context and per local reference ranges. †—LH and FSH may be normal in functional hypothalamic amenorrhea. Adapted with permission from Gordon CM, Ackerman KE, Berga SL, et al. Functional hypothalamic amenorrhea: ​an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2017;​102(5):​1423.

and constitutional delay, have been described previously in Healthy eating habits and regular exercise should be rec- American Family Physician.5 ommended for all patients with PCOS. Weight loss may restore regular menses and improve metabolic comorbidi- OTHER ENDOCRINE CAUSES ties in patients with an elevated body mass index.12,49,50 Com- Polycystic Ovary Syndrome. PCOS is a multifactorial endocrine bined hormonal contraceptives are first-line therapy for disorder characterized by ovulatory dysfunction, biochemical menstrual abnormalities, hirsutism, acne, and protection or clinical androgen access, and polycystic ovaries.6,8,12,49 The from endometrial cancer caused by unopposed estrogen Rotterdam Consensus Criteria require two of the aforemen- secretion.12,14,49,50 Metformin may prevent diabetes mellitus tioned features for diagnosis;​ the Androgen Excess Society and regulate menses, and it may be appropriate for patients requires hyperandrogenism and another feature.8,12,49 Pelvic with impaired glucose tolerance when lifestyle modifica- ultrasonography is not required for diagnosis.8,49,50 Diagnos- tion is unsuccessful or for those with contraindications tic accuracy in adolescence is challenging because anovula- to applicable contraceptives.12,49 Metformin is ineffective tion and polycystic ovarian morphology can be physiologic;​ for treating acne or hirsutism.15,49 For patients with PCOS therefore, hyperandrogenism and persistent oligomenorrhea and infertility, letrozole (Femara) is a first-line therapeutic are key to diagnosis.8,49 Benefits of early management may option, because it confers higher ovulation, pregnancy, and outweigh risks of delay for diagnostic certainty.8,49 live birth rates than clomiphene.12,50,52 Markedly elevated serum androgens could indicate other Thyroid and Adrenal Disease. Hypo- and hyperthyroidism hyperandrogenic conditions, but strict cut-offs are not may cause amenorrhea.2,6,12 Late-onset congenital adrenal defined.2,12,49 PCOS is associated with metabolic syndrome hyperplasia (e.g., 21-hydroxylase deficiency) is a common and resistance. Patients should be screened for cause of hyperandrogenic amenorrhea;​ an elevated serum hypertension and an elevated body mass index at each visit, 17-hydroxyprogesterone level should be followed by con- and should be screened for dyslipidemia and impaired glu- firmatory adrenocorticotropic hormone stimulation test- cose tolerance (i.e., two-hour oral glucose tolerance testing ing.12,49,53 Adrenal or ovarian androgen-secreting tumors are [preferred] or A1C level) every three to five years.12,49-51 exceedingly rare but should be considered in patients with

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SORT:​ KEY RECOMMENDATIONS FOR PRACTICE

Evidence Clinical recommendation rating Comments

Patients who have not reached menarche by 15 years of age (or three years post- C Recommendation from consensus thelarche), or who have experienced cessation of regular menses for three months guidelines or previously irregular menses for six months, should be evaluated.1,3,4,6

Pregnancy should be excluded in all patients with amenorrhea, and serum folli- C Recommendation from consensus cle-stimulating hormone, luteinizing hormone, prolactin, and thyroid-stimulating guidelines hormone levels should be obtained.1-3,6,10-12

Patients with primary ovarian insufficiency should be treated with hormone therapy C Recommendation from consensus guide- until the age of natural menopause (50 to 51 years of age) to reduce the risk of line based on observational studies and a , cardiovascular disease, and urogenital atrophy.36-39 randomized controlled trial

In patients with functional hypothalamic amenorrhea, treatment should correct B Recommendations from consensus the underlying cause to restore ovulatory function through behavior change, nutri- guideline based on observational studies tional repletion (e.g., caloric intake, vitamin D), stress reduction, and weight gain.2,22

In patients with functional hypothalamic amenorrhea, combined oral contraceptives C Recommendations from consensus guide- do not improve bone density and should not be used solely for this purpose.2,22,47,48 line based on a randomized controlled trial (disease-oriented outcome) and a system- atic review of observational studies

In patients with polycystic ovary syndrome and an elevated body mass index, weight B Recommendation from consensus guide- loss and regular exercise are recommended and may restore regular menses and lines based on observational studies and improve metabolic comorbidities.12,49,50 randomized controlled trials

In patients with polycystic ovary syndrome and infertility, letrozole (Femara) is a A Recommendation from consensus first-line treatment because it confers higher ovulation, pregnancy, and live birth guidelines based on meta-analysis of rates than clomiphene.12,50,52 randomized trials

A = consistent, good-quality patient-oriented evidence;​ B = inconsistent or limited-quality patient-oriented evidence;​ C = consensus, disease- oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.​ org/afpsort.

rapid-onset virilization or markedly elevated serum andro- clinical trials, and reviews published after August 1, 2011. Also gens.3,12,49 If physical stigmata of excess are present, searched were Essential Evidence Plus, and the Cochrane Data- base of Systematic Reviews. Search dates:​ April 18 to July 16, Cushing syndrome may be excluded by a 24-hour urinary 2018, and January 20, 2019. free cortisol, late-night salivary cortisol, or dexamethasone suppression test.2,12,49 The contents of this article are solely the views of the authors and do not necessarily represent the official views of the Uni- Chronic Disease, Physiologic, and Induced formed Services University of the Health Sciences, the U.S. Air Causes Force, the U.S. Army, the U.S. Navy, the U.S. military at large, the U.S. Department of Defense, or the U.S. government. Patients with chronic disease may experience amenorrhea; ​ however, these conditions are often recognized by individ- The Authors ual signs and symptoms. Menopause should be considered in patients older than 40 years.15,16,54 Pregnancy, , DAVID A. KLEIN, MD, MPH, is an associate program director hormonal contraceptives, and exogenous androgens (e.g., of the National Capital Consortium Family Medicine Resi- transgender care) may also cause amenorrhea.2,3,6 dency Program at Fort Belvoir (Va.) Community Hospital and an assistant professor in the Departments of Family Medicine This article updates previous articles on this topic by Klein and and Pediatrics at the Uniformed Services University of the Poth,3 and Master-Hunter and Heiman.55 Health Sciences, Bethesda, Md. Data Sources: ​ A PubMed search was completed using the MeSH SCOTT L. PARADISE, MD, is a third-year resident in the function with the key phrase amenorrhea and one of the fol- National Capital Consortium Family Medicine Residency Pro- lowing: ​diagnosis, evaluation, management, or treatment. The gram at Fort Belvoir Community Hospital. search included meta-analyses, randomized controlled trials,

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18. Nelson SM. Biomarkers of ovarian response:​ current and future applica- RACHEL M. REEDER, MD, is a third-year resident in the tions. Fertil Steril. 2013;​99(4):​963-969. National Capital Consortium Family Medicine Residency Pro- 19. Tosi F, Fiers T, Kaufman JM, et al. Implications of androgen assay accu- gram at Fort Belvoir Community Hospital. racy in the phenotyping of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2016;101(2):​ 610-618.​ Address correspondence to David A. Klein, MD, MPH, Fort 20. Gravholt CH, Andersen NH, Conway GS, et al.; ​International Turner Syn- Belvoir Community Hospital, 9300 DeWitt Loop, Fort Belvoir, drome Consensus Group. Clinical practice guidelines for the care of VA 22060 (e-mail:​ david.a.klein26.mil@​mail.mil). Reprints are girls and women with Turner syndrome:​ proceedings from the 2016 not available from the authors. Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol. 2017;177(3):​ G1-G70.​ 21. 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38. Committee on Gynecologic Practice. Committee opinion no. 698:​ hor- 48. Altayar O, Al Nofal A, Carranza Leon BG, Prokop LJ, Wang Z, Murad MH. mone therapy in primary ovarian insufficiency.Obstet Gynecol. 2017;​ Treatments to prevent bone loss in functional hypothalamic amenor- 129(5):e134-e141.​ rhea: ​a systematic review and meta-analysis. J Endocr Soc. 2017;1(5):​ ​ 39. Burgos N, Cintron D, Latortue-Albino P, et al. Estrogen-based hormone 500-511. therapy in women with primary ovarian insufficiency:​ a systematic 49. Legro RS, Arslanian SA, Ehrmann DA, et al. Diagnosis and treatment review. Endocrine. 2017;58(3):​ 413-425.​ of polycystic ovary syndrome: ​an Endocrine Society clinical practice 40. Canonico M, Oger E, Plu-Bureau G, et al.;​ Estrogen and Thrombo- guideline. J Clin Endocrinol Metab. 2013;​98(12):​4565-4592. embolism Risk (ESTHER) Study Group. Hormone therapy and venous 50. Teede HJ, Misso ML, Costello MF, et al.;​ International PCOS Network. thromboembolism among postmenopausal women:​ impact of the Recommendations from the international evidence-based guideline for route of estrogen administration and progestogens: ​the ESTHER study. the assessment and management of polycystic ovary syndrome. Hum Circulation. 2007;115(7):​ 840-845.​ Reprod. 2018;​33(9):​1602-1618. 41. Camacho PM, Petak SM, Binkley N, et al. American Association of Clin- 51. Jellinger PS, Handelsman Y, Rosenblit PD, et al. American Association ical Endocrinologists and American College of Endocrinology clinical of Clinical Endocrinologists and American College of Endocrinology practice guidelines for the diagnosis and treatment of postmenopausal guidelines for management of dyslipidemia and prevention of cardio- osteoporosis - 2016. Endocr Pract. 2016;22(suppl​ 4):1-42.​ vascular disease. Endocr Pract. 2017;23(suppl​ 2):1-87.​ 42. Alper MM, Jolly EE, Garner PR. after premature ovarian fail- 52. Hu S, Yu Q, Wang Y, Wang M, Xia W, Zhu C. Letrozole versus clomiphene ure. Obstet Gynecol. 1986;​67(3 suppl):​59S-62S. citrate in polycystic ovary syndrome:​ a meta-analysis of randomized 43. Rovinski D, Ramos RB, Fighera TM, Casanova GK, Spritzer PM. Risk controlled trials. Arch Gynecol Obstet. 2018;297(5):​ 1081-1088.​ of venous thromboembolism events in postmenopausal women 53. Hannah-Shmouni F, Morissette R, Sinaii N, et al. Revisiting the preva- using oral versus non-oral hormone therapy: ​A systematic review and lence of nonclassic congenital adrenal hyperplasia in US Ashkenazi meta-analysis. Thromb Res. 2018;​168:​83-95. Jews and Caucasians. Genet Med. 2017;​19(11):​1276-1279. 44. Gibbs JC, Nattiv A, Barrack MT, et al. Low bone density risk is higher in 54. Chaudhry S, Tadokoro-Cuccaro R, Hannema SE, Acerini CL, Hughes exercising women with multiple triad risk factors. Med Sci Sports Exerc. IA. Frequency of gonadal tumours in complete androgen insensitivity 2014;​46(1):​167-176. syndrome (CAIS):​ a retrospective case-series analysis. J Pediatr Urol. 45. Kandemir N, Slattery M, Ackerman KE, et al. Bone parameters in anorexia 2017;13(5):​ 498.e1-498.e6.​ nervosa and athletic amenorrhea: ​comparison of two hypothalamic 55. Master-Hunter T, Heiman DL. Amenorrhea: ​evaluation and treatment. amenorrhea states. J Clin Endocrinol Metab. 2018;​103(6):​2392-2402. Am Fam Physician. 2006;​73(8):​1374-1382. 46. Chamberlain R. The female athlete triad: ​recommendations for man- agement. Am Fam Physician. 2018;97(8):​ 499-502.​ 47. Misra M, Katzman D, Miller KK, et al. Physiologic estrogen replace- ment increases bone density in adolescent girls with anorexia nervosa. J Bone Miner Res. 2011;​26(10):​2430-2438.

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eTABLE A

The Female Athlete Triad:​ Proposed Tool to Guide Return to Play Recommendations* Magnitude of risk

Risk factors Low risk = 0 points each Moderate risk = 1 point each High risk = 2 points each

Low energy availability with No dietary restriction Some dietary restriction;​ current or Meets DSM-5 criteria for current or or without an eating disorder history of disordered eating history of an eating disorder

Low BMI or expected weight BMI ≥ 18.5 kg per m2, BMI 17.5 kg per m2 to < 18.5 kg per BMI ≤ 17.5 kg per m2, < 85% expected ≥ 90% expected weight, m2, < 90% expected weight, or 5% to weight, or ≥ 10% weight loss per month or weight stable < 10% weight loss per month

Delayed menarche Menarche < 15 years Menarche 15 to < 16 years Menarche ≥ 16 years

Oligomenorrhea or amenor- > 9 menses in 12 months 6 to 9 menses in 12 months < 6 menses in 12 months rhea (current or history)

Low bone mineral density† Z-score ≥ –1.0 Z-score –1.0 to < –2.0, especially in Z-score ≤ –2.0 weight-bearing sports

Stress reaction/fracture None 1 2 or more, or 1 high-risk fracture (e.g., trabecular site such as femoral neck, sacrum, or )

Cumulative risk # Points + # Points + # Points = Total Score

Note:​ BMI percentile (based on 50th percentile population measurements) is used to calculate expected weight for individuals younger than 20 years. A calculator can be found at: ​https://www.cdc.gov/healthyweight/bmi/calculator.html​ . BMI = body mass index;​ DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Full clearance = 0 to 1 point;​ provisional or limited clearance = 2 to 5 points; ​restricted from training or competition = 6 or more points. *—The athlete’s overall clinical and psychosocial context should guide application of this proposed decision tool. Athletes with an eating disorder and BMI < 16 kg per m2 or an athlete who is purging more than 4 times per week should be categorically restricted from training and participation. †—Bone density testing is indicated for individuals with 2 or more moderate risk factors or 1 high risk factor. Osteoporosis is defined as a bone mineral density Z-score of –2.0 or less (or –1.0 or less if weight-bearing sport) and a clinically significant stress fracture (5 to 19 years of age) or presence of a secondary cause (20 years or older). Adapted with permission from De Souza MJ, Nattiv A, Joy E, et al.;​ Expert Panel. 2014 female athlete triad coalition consensus statement on treat- ment and return to play of the female athlete triad: ​1st international conference held in San Francisco, California, May 2012 and 2nd international conference held in Indianapolis, Indiana, May 2013. Br J Sports Med. 2014;48(4):​ 289.​

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